Mouse TRPA1 function and membrane localization is modulated by direct interactions with cholesterol

The cation channel TRPA1 transduces a myriad of noxious chemical stimuli into nociceptor electrical excitation and neuropeptide release, leading to pain and neurogenic inflammation. Despite emergent evidence that TRPA1 is regulated by the membrane environment, it remains unknown whether this channel localizes in membrane microdomains or whether it interacts with cholesterol. Using total internal reflection fluorescence microscopy and density gradient centrifugation we found that mouse TRPA1 localizes preferably into cholesterol-rich domains and functional experiments revealed that cholesterol depletion decreases channel sensitivity to chemical agonists. Moreover, we identified two structural motifs in transmembrane segments 2 and 4 involved in mTRPA1-cholesterol interactions that are necessary for normal agonist sensitivity and plasma membrane localization. We discuss the impact of such interactions on TRPA1 gating mechanisms, regulation by the lipid environment, and role of this channel in sensory membrane microdomains, all of which helps to understand the puzzling pharmacology and pathophysiology of this channel.
Source: eLife - Category: Biomedical Science Tags: Biochemistry and Chemical Biology Neuroscience Source Type: research

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Source: Biomedical Microdevices - Category: Biomedical Engineering Authors: Tags: Biomed Microdevices Source Type: research
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Source: The Tox Cave - Category: Emergency Medicine Tags: Blog Posts Source Type: blogs
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Source: The Journal of Head Trauma Rehabilitation - Category: Neurology Tags: Original Articles Source Type: research
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Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
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Source: European Spine Journal - Category: Orthopaedics Source Type: research
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Source: Medicine and Science in Sports and Exercise - Category: Sports Medicine Tags: APPLIED SCIENCES Source Type: research
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Source: Journal of Nutrition and Metabolism - Category: Nutrition Tags: J Nutr Metab Source Type: research
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Source: The British Journal of Psychiatry for Mental Science - Category: Psychiatry Tags: Br J Psychiatry Source Type: research
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